Neurotransmitter transporters play a critical role in the regulation of synaptic transmission. These transporters, which are located on the pre-synaptic terminal and surrounding glial cells, sequester neurotransmitter from the synapse, thereby regulating the synaptic concentration of neurotransmitter and influencing the duration and magnitude of synaptic transmission. Transporters also help to limit the extent of synaptic transmission by preventing the spread of transmitter to neighboring synapses. In view of the important role played by these transporters in neurological function, they represent attractive targets for pharmacological modulation, potentially providing novel methods of treatment for any of a number of psychological and neurological conditions.
The amino acid glycine functions at both inhibitory and excitatory synapses in the central and peripheral nervous systems of mammals. The excitatory and inhibitory functions of glycine are mediated by two different types of receptor, each of which is associated with a different type of glycine transporter. At excitatory synapses, glycine acts as an obligatory co-agonist at a class of glutamate receptors called N-methyl-D-aspartate (NMDA) receptors. Activation of these receptors in neurons increases sodium and calcium conductance, thereby depolarizing the neuron and increasing the likelihood that the neuron will fire an action potential.
The class of glycine transporter thought to be involved in excitatory synapses in conjunction with NMDA receptors is Glyt-1. At least four variants of GlyT-1 (GlyT-1a, GlyT-1b, GlyT-1c, and Glyt-1d), have been described. Both GlyT1 and GlyT2 transporters are members of a broader family of sodium- and chloride-dependent neurotransmitter transporters, the members of which typically have 12 transmembrane domains (Olivares et al. (1997) J. Biol. Chem. 272:1211-1217; Uhl, Trends in Neuroscience 15: 265-268, 1992; Clark et al, BioEssays 15: 323-332, 1993). Both the N- and C-termini of the members of this family are thought to be intracellular.
NMDA receptor activity has been implicated in a large number of psychological and neurological functions, such as learning and memory, and in a large number of diseases and conditions, including schizophrenia, dementias, attention-deficit hyperactive disorder, and various neurodegenerative disorders. Thus, modulators of GlyT1 proteins can used to treat these and other conditions. The present invention addresses these and other needs.